VCAM-1 is also a mediator of chronic inflammatory disorders such as asthma, rheumatoid arthritis, autoimmune diabetes and multiple sclerosis. For example, it is known that the expression of VCAM-1 and ICAM-1 are increased in asthmatics (Pilewski, J. M., et al. Am. J. Respir. Cell Mol. Biol. 12, 1–3 (1995); Ohkawara, Y., et al., Am. J. Respir. Cell Mol. Biol. 12, 4–12 (1995)). Additionally, blocking the integrin receptors for VCAM-1 and ICAM-1 (VLA-4 and LFA-1, respectively) suppressed both early and late phase responses in an ovalbumin-sensitized rat model of allergic airway responses (Rabb, H. A., et al., Am. J. Respir. Care Med. 149, 1186–1191 (1994)). There is also increased expression of endothelial adhesion molecules, including VCAM-1, in the microvasculature of rheumatoid synovium (Koch, A. E. et al., Lab. Invest. 64, 313–322 (1991); Morales-Ducret, J. et al., Immunol. 149, 1421–1431 (1992)). Neutralizing antibodies directed against VCAM-1 or its counter receptor, VLA-4, can delay the onset of diabetes in a mouse model (NOD mice) which spontaneously develops the disease (Yang, X. D. et al., Proc. Natl. Acad. Sci. U.S.A. 90, 10494–10498 (1993); Burkly, L. C. et al., Diabetes 43, 523–534 (1994); Baron, J. L. et al., J. Clin. Invest. 93, 1700–1708 (1994)).
VCAM-1 is expressed by cells both as a membrane bound form and as a soluble form. The soluble form of VCAM-1 has been shown to induce chemotaxis of vascular endothelial cells in vitro and stimulate an angiogenic response in rat cornea (Koch, A. F. et al., Nature 376, 517–519 (1995)). Inhibitors of the expression of soluble VCAM-1 have potential therapeutic value in treating diseases with a strong angiogenic component, including tumor growth and metastasis (Folkman, J. and Shing, Y., Biol. Chem. 10931–10934 (1992)).
VCAM-1 is expressed in cultured human vascular endothelial cells after activation by lipopolysaccharide (LPS) and cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF-alpha).
It has been documented that VCAM-1 is expressed on brain microvessel endothelial cells in active lesions of multiple sclerosis brain. Multiple sclerosis is a common demyelinating disorder of the central nervous system, causing patches of sclerosis (plaques) in the brain and spinal cord. It occurs in young adults and has protean clinical manifestations. Experimental therapy using antibodies for VCAM-1 in autoimmune encephalomyelitis, which is an animal model for multiple sclerosis, has shown that adhesion molecules play a role in the pathogenesis of the disease (Benveniste et al., J. Neuroimmunol. 98:77–88, 1999). Time and dose dependent expression of VCAM-1 and release of soluble VCAM-1 were detected in cultures of human cerebral endothelial cells induced by TNF-alpha, but not in peripheral blood mononuclear cells (Kallmann et al., Brain 123:687–697, 2000). Clinical data also show that adhesion molecules in blood and cerebrospinal fluid are up-regulated throughout the clinical spectrum of multiple sclerosis, further supporting the belief that multiple sclerosis can be suppressed by interfering with cell adhesion molecules such as VCAM-1 (Elovaara et al., Arch. Neurol. 57:546–551, 2000).
A variety of agents have been reported as potent inhibitors of VCAM-1 expression. (Schreiner et al., Expert Opi. Ther. Patents 2003, 13, 149–166; Meng et al., Bioorg. Med. Chem. Lett. 2001, 11, 1823–1827.) A cyclic depsipeptide effectively inhibited VCAM-1 expression and reduced inflammation in a dermal model of inflammation (Foster et al., Skin Pharmacol. 1996, 9, 149). A monoclonal antibody against VCAM-1 inhibited neointimal formation in a murine model of arterial wall injury. (Oguchi et al., Arterioscler. Thromb. Vasc. Biol. 2000, 20, 1729–1736.) A disubstituted 1,4-diazepine diminished the increase in paw swelling in a mouse model of collagen-induced arthritis. (Nakao et al., J. Atheroscler. Thromb. 1998, 4, 149–155.) Some VLA-4 antagonists have shown efficacy in animal models of disease. CP-664511, a small-molecule VLA-4 antagonist in clinical trials in asthmatic patients, inhibited airway eosinophil infiltration in a murine model of allergic pulmonary inflammation. (Kudlacz et al., J. Pharmacol. Exp. Ther. 2002, 301, 747–752.) Several activators of peroxisome proliferator-activated receptors (PPARs) inhibited the expression of VCAM-1 on endothelial cells, suggesting a role of VCAM-1 in the anti-inflammatory response of PPAR activation. (Marx et al., J. Cardiovasc. Risk 2001, 8, 203–210; and Rival et al., Eur. J. Pharmacol. 2002, 435, 143–151.)
Probucol has been shown to possess potent antioxidant properties and to block oxidative modification of LDL. Consistent with these findings, probucol has been shown to actually slow the progression of atherosclerosis in LDL receptor-deficient rabbits. (Carew et al. Proc. Natl. Acad. Sci. U.S.A. 84:7725–7729 (1987); Meng, C. Q. Probucol (Restenosis). Curr. Opin. Cardiovasc. Pulm. Renal Invest. Drugs 2000, 2, 294–298; Barnhart et al., The Synthesis, Metabolism, and Biological Activity of Probucol and Its Analogs. In Antilipidemic Drugs: Medicinal, Chemical, and Biochemical Aspects, Witiak et al., Eds., Elsevier Science: Amsterdam, 1991, pp 277–299.)
Probucol is chemically related to the widely used food additives 2,(3)-tert-butyl-4-hydroxyanisole (BHA) and 2,6-di-tert-butyl-4-methyl phenol (BHT). It is a thioketal having a chemical name of 4,4′-(isopropylidenedithio) bis(2,6-di-tert-butylphenol) and has the following chemical structure:

While probucol is a potent chemical anti-oxitant, there is little data to indicate it can be used in inflammatory diseases that do not depend on changing lipid levels such as sheumatoid arthritis, asthma and COPD. It is used primarily to lower serum cholesterol levels in hypercholesterolemic patients. Probucol is commonly administered in the form of tablets available under the trademark Lorelco™.
U.S. Pat. No. 5,262,439 to Parthasarathy discloses analogs of probucol with increased water solubility in which one or both of the hydroxyl groups are replaced with ester groups.
Certain probucol ester derivatives have been described as being hypocholesterolemic and hypolipidemic agents: Fr 2168137 (bis 4-hydroxyphenylthioalkane esters); Fr 2140771 (tetralinyl phenoxy alkanoic esters of probucol); Fr 2140769 (benzofuryloxyalkanoic acid derivatives of probucol); Fr 2134810 (bis-(3-alkyl-5-t-alkyl-4-thiazole-5-carboxy)phenyl-thio)alkanes; FR 2133024 (bis-(4-nicotinoyloxyphenylthio)propanes; and Fr 2130975 (bis(4-(phenoxyalkanoyloxy)-phenylthio)alkanes).
De Meglio et al. have described several ethers of symmetrical molecules for the treatment of hyperlipidemia. These molecules contain two phenyl rings attached to each other through a —S—C(CH3)2—S— bridge. In contrast to probucol, the phenyl groups do not have t-butyl as substituents. (De Meglio et al., New Derivatives of Clofibrate and probucol: Preliminary Studies of Hypolipemic Activity; Farmaco, Ed. Sci (1985), 40 (11), 833–44).
WO 00/26184 discloses a large genus of compounds with a general formula of phenyl-S-alkylene-S-phenyl, in which one or both phenyl rings can be substituted at any position. These compounds were disclosed as lubricants.
U.S. Pat. Nos. 5,750,351; 5,807,884; 5,811,449; 5,846,959; 5,773,231, and 5,773,209 to Medford, et al. (assigned to Emory University), as well as the corresponding WO95/30415 to Emory University indicate that polyunsaturated fatty acids (“PUFAs”) and their hydroperoxides (“ox-PUFAs”), which are important components of oxidatively modified low density lipoprotein (LDL), induce the expression of VCAM-1, but not intercellular adhesion molecule-1 (ICAM-1) or E-selectin in human aortic endothelial cells.
U.S. Pat. No. 5,155,250 to Parker et al. discloses that 2,6-dialkyl-4-silylphenols are antiatherosclerotic agents. The same compounds are disclosed as serum cholesterol lowering agents in PCT Publication No. WO 95/15760, published on Jun. 15, 1995. U.S. Pat. No. 5,608,095 to Parker et al. discloses that alkylated-4-silyl-phenols inhibit the peroxidation of LDL, lower plasma cholesterol, and inhibit the expression of VCAM-1, and thus are useful in the treatment of atherosclerosis.
A series of European patent applications of Shionogi Seiyaku Kabushiki Kaisha disclose phenolic thioethers for use in treating arteriosclerosis. European Patent Application No. 348 203 discloses phenolic thioethers which inhibit the denaturation of LDL and the incorporation of LDL by macrophages. The compounds are useful as anti-arteriosclerosis agents. Hydroxamic acid derivatives of these compounds are disclosed in European Patent Application No. 405 788 and are useful for the treatment of arteriosclerosis, ulcer, inflammation and allergy. Carbamoyl and cyano derivatives of the phenolic thioethers are disclosed in U.S. Pat. No. 4,954,514 to Kita et al.
U.S. Pat. No. 4,752,616 to Hall et al. discloses arylthioalkylphenylcarboxylic acids for the treatment of thrombotic disease. The compounds disclosed are useful as platelet aggregation inhibitors for the treatment of coronary or cerebral thromboses and the inhibition of bronchoconstriction, among others.
A series of patents to Adir et Compagnie disclose substituted phenoxyisobutyric acids and esters useful as antioxidants and hypolipaemic agents. This series includes U.S. Pat. Nos. 5,206,247 and 5,627,205 to Regnier, et al. (which corresponds to European Patent Application No. 621 255) and European Patent Application No. 763 527.
WO 97/15546 to Nippon Shinyaku Co. Ltd. discloses carboxylic acid derivatives for the treatment of arterial sclerosis, ischemic heart diseases, cerebral infarction and post PTCA restenosis.
The Dow Chemical Company is the assignee of patents to hypolipidemic 2-(3,5-di-tert-butyl-4-hydroxyphenyl)thio carboxamides. For example, U.S. Pat. Nos. 4,029,812, 4,076,841 and 4,078,084 to Wagner, et al., disclose these compounds for reducing blood serum lipids, especially cholesterol and triglyceride levels.
PCT WO 98/51289, filed by Emory University and listing as inventors Russell M. Medford and Patricia K. Somers, claims priority to provisional patent application U.S. Ser. No. 60/047,020, filed on May 14, 1997. This application discloses that monoesters of probucol inhibit the expression of VCAM-1, and may also exhibit the composite profile of lowering LDL and reducing cholesterol.
Recent reports demonstrated that mono-esters potently inhibited cytokine-induced VCAM-1 and MCP-1 expression and smooth muscle cell proliferation in vitro, and progression of atherosclerosis in experimental animals. (Meng et al., Bioorg. Med. Chem. Lett. 2002, 12, 2545–2548. In clinical trials, AGI-1067 did not cause QTc prolongation, while probucol did. Tardif et al., Circulation 2003, 107, 552–558.)
PCT WO 98/51662 and U.S. Pat. Nos. 6,147,250, 6,548,699, 6,617,352 and 6,602,914 describe mono-esters of probucol for the treatment of VCAM-1 mediated diseases including cardiovascular and inflammatory diseases. PCT US 01/09049 discloses thioketals and thioethers for the treatment of VCAM-1 mediated diseases including inflammatory disorders.
There is a need for new phenolic compounds that can be used in the treatment of a variety of disorders.